Prostaglandin (PG) endoperoxides (e.g. PGH2) are pivotal intermediates in the biosynthesis of prostaglandins, ubiquitous human hormone-like derivatives of polyunsaturated fatty acids. Although PGs were known to mediate cardiovascular phenomena, it was only recently discovered that the endoperoxides have a direct role in blood chemistry via thromboxane A2 (TXA2) and prostacyclin (PGI2) which are produced from the endoperoxide PGH2 under the influence of enzymes in platelets or blood vessel tissue respectively. The mechanisms of these transformations are not known. Our successful development of several syntheses of the nucleus of PG endoperoxides and studies of its chemical reactions have clearly shown that the chemistry of this strained bicyclic peroxide is unique and cannot be predicted by simple extrapolation of the behavior of any other dialkyl peroxide. Similar work on the novel and reactive bicyclic acetal nucleus of TXA2 is planned as are studies on more complex models as well as on naturally derived PGH2 and TXA2. These model studies provide crucial insights which suggest simple explanations for several reports of unidentified metabolites from arachidonic acid. Thus an unidentified non-TXA2 derivative of PGH 2 is reported to bind to tissue macromolecules and glutathione. We postulate that the metabolite may be a levulinaldehyde derivative of PGH2 (a levuglandin) since the PG endoperoxide nucleus undergoes facile rearrangement to levulinaldehyde under physiological conditions and the latter forms covalent adducts with primary amino acids. Levuglandins provide a simple explanation for an arachidonic acid metabolite produced in the presence of chick epiphyseal cartilage microsomes or rat renal microsomes. Most importantly, we now have shown that PGH2 does rearrange to give LGE2 and LGD2. This spectacular discovery makes it possible for us to test our hypotheses by direct comparisons with authentic levuglandins. The proposed synthetic and mechanistic studies as well as collaborative studies on structure-activity relationships for the biological activities of models, analogues, as well as authentic levuglandins will provide a fundamental understanding of PG endoperoxide, thromboxane, and levuglandin biochemistry.